Alpha-fetoprotein (AFP), a protein produced by the fetal liver, is one of the agents of pregnancy that affords significant reduction in risk of acquiring breast cancer to women who experience term pregnancy. AFP stops the growth of estrogen-dependent human breast cancer xenografts. It is non-toxic, and its mechanism of action is different from that of agents currently used in the clinic to treat breast cancer. We have designed a novel cyclic synthetic peptide, AFPep, which mimics the anti-oncotic active site of AFP. AFPep inhibits the growth of T47D breast cancer cells in culture and inhibits the growth of MCF-7 human breast cancer growing as xenografts in mice. AFPep has a novel mechanism (i.e., is different from tamoxifen and does not bind to the estrogen receptor), and it blocks tamoxifen-stimulated uterine growth. Proof-of-principle data exist to suggest that AFPep can prevent breast cancer in a rat model. The Iong-term objective of the research program is to develop AFPep (or peptidomimetic analogs of AFPep) for use in the treatment and prevention of breast cancer in women. The hypothesis of this proposal is that administration of AFPep (or peptidomimetic analogs) in combination with tamoxifen to carcinogen (NMU) treated rats will augment cancer chemoprevention efficacy and reduce host toxicity compared to that of tamoxifen alone. The specific aims are: 1.) To compare the ability of AFPep, and that of tamoxifen, to prevent NMU-induced breast cancer in the rat model; 2.) To develop orally active analogs of AFPep (peptidomimetics) and test prevention capability in the rat model; and 3.) To assess safety of the peptide and analogs by obtaining preliminary toxicity measurements. The research design is to use a well-documented assay in which carcinogen-induced rats are treated with vehicle, AFPep, tamoxifen, or AFPep plus tamoxifen. Endpoints will include tumor latency (increased time to first tumors) and tumor burden (decreased incidence) for efficacy, and decreased uterotrophic response to tamoxifen for host toxicity. Health related aspects of the proposal include the observation that there is need for additional agents, with novel mechanisms of action, for the prevention of estrogen-receptor positive breast cancer. The need is emphasized by the observation that currently used chemopreventives for breast cancer are not without adverse side effects. AFPep has the potential to be used in combination with tamoxifen or as a stand-alone preventive agent. Its development and introduction to the clinic could prevent as many as 50,000 cases of breast cancer every year.